Epstein-Barr Virus (EBV) is a ubiquitous human herpesvirus that is associated with malignancies of both lymphoid and epithelial origin including Burkitt's lymphoma and nasopharyngeal carcinoma (NPC) among others. The focus of this study was to investigate both EBV and rhesus EBV (LCV) latent membrane protein 2A (LMP2A) signaling and biological functions in epithelial cells and their contribution to EBV-mediated carcinogenesis. Rhesus LCV LMP2A (Rh-LMP2A) has an overall sequence homology of 62% to EBV LMP2A. The 12 transmembrane domains and the N-terminal cytoplasmic domain containing an immunoreceptor tyrosine-based activation motif (ITAM) and PY motifs are conserved in Rh-LMP2A. In this study, Rh-LMP2A expression in human foreskin keratinocytes (HFK) activated Akt and inactivated GSK3[beta]. This led to the subsequent accumulation and nuclear translocation of [beta]-catenin which was found to be Akt dependent. Rh-LMP2A also inhibited epithelial cell differentiation. A mutant form of Rh-LMP2A lacking the last six transmembrane domains was able to function similarly to full-length Rh-LMP2A. Since EBV LMP2A is consistently expressed in metastatic NPC, the potential role of LMP2A in metastasis was investigated. EBV LMP2A expression in HFK cells led to increased expression and activity of several matrix metalloproteinases (MMPs), which are involved in basement membrane and extracellular matrix degradation. The activity of MMP-7 and MMP-13 was dependent on Akt activation, whereas MMP-2 activity was dependent on MAPK activation. These results identify a mechanism by which EBV LMP2A could contribute to NPC metastasis. Through the activation of the PI3K/Akt and [beta]-catenin pathways that impact cell proliferation and survival in addition to upregulating MMP expression and activity, LMP2A likely contributes to carcinogenesis and metastasis. Lastly, the similarity of rhesus LCV to EBV further validates the rhesus macaque model for the study of EBV pathogenesis
